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"I have been very happily surprised to see more and more physicians contacting me and saying they have patients with cystinosis and are very interested to be part of the next phase when the trial will be multicenter and this is really good to see. So, there is a growing interest from physicians to our gene therapy.”

AVROBIO's CTNS-RD-04 is being evaluated in an ongoing phase 1/2 trial (NCT03897361) for the potential treatment of cystinosis. The autologous, lentiviral, CD34+ cell therapy encodes forcystinosin to prevent the buildup of cysteine crystals.

Principal investigator Stephanie Cherqui, PhD, associate professor, University of California – San Diego, presented interim data from the first 3 patients treated in the trial at the 18th Annual WORLDSymposium, February 7-11, 2022, in San Diego, California. All patients exhibited a decrease in white blood cell cystine and are no longer taking oral cysteamine and promising decreases in cystine were noted in the cornea, skin, and kidneys. The therapy has been well-tolerated and no treatment-related adverse events (AEs) or serious AEs have been reported.

 spoke with Cherqui to learn more about the efficacy and safety data seen in the trial so far. She also discussed a growing clinician interest in the therapy and cystinosis itself.

Cherqui S. Hematopoietic stem cell gene therapy for cystinosis: Updated results from a phase I/II clinical trial. Presented at: 18th Annual WORLDSymposium, February 7-11, 2022; San Diego, CA. Poster #46

The associate professor from UC San Diego discussed promising efficacy and safety data from a phase 1/2 trial. 

Stephanie Cherqui, PhD, on Bringing Attention to Cystinosis and Gene Therapy 

"For the stem cell manufacturing, the patients come to UCSD and they go through stem cell mobilization, and we take out their white blood cells during leukapheresis. The white blood cells is transported to the good manufacturing practice facility at UCLA where the CD44 hematopoietic cells are gene modified using a lentivirus vector.”

AVROBIO is developing CTNS-RD-04, an autologous, lentiviral, CD34+ cell therapy encoding for cystinosin for the potential treatment of cystinosis. Stephanie Cherqui, PhD, associate professor, University of California – San Diego, is developing the therapy in her lab and evaluating it for safety and efficacy in an ongoing phase 1/2 trial (NCT03897361).

Cherqui presented interim data from the first 3 patients treated in the trial at the 18th Annual WORLDSymposium, February 7-11, 2022, in San Diego, California. No treatment-related adverse events (AEs) or serious AEs have been reported. All patients exhibited a decrease in white blood cell cystine and are no longer taking oral cysteamine. Promising decreases in cystine were also noted in the cornea, skin, and kidneys.

spoke with Cherqui to learn more about the trial, including trial protocols and CTNS-RD-04's mechanism of action.

The associate professor from UC San Diego discussed the ongoing phase ½ trial of CTNS-RD 

Assessing Lentiviral Cell Therapy for Cystinosis: Stephanie Cherqui, PhD 

“We have developed a complex pipeline that starts from the bone marrow of the patients, and goes all the way to cellular processing, molecular processing, sequencing and computational analysis to deliver a comprehensive overview on how the engineered cells behave, and where they reside once we infuse them into the patient.”

AVROBIO is prioritizing molecular follow-up of lentiviral cell therapies in patients with lysosomal disease with the use of their new analytical pipeline that elucidates cell therapy destiny and distribution. Luca Biasco, PhD, director, research and development, AVROBIO, presented an overview of the pipeline at the 18th Annual WORLDSymposium, February 7-11, 2022 in San Diego, CA.

As part of the analytical pipeline, Biasco and colleagues conducted high-resolution cellular and molecular studies on bone marrow and peripheral blood before and after lentiviral cell therapy treatment. They analyzed subpopulations of bone marrow and peripheral blood cells via digital PCR-vector copy number and integration site analysis, as also used clonal tracking data to elucidate the dynamics and destiny of cell populations after gene therapy.

spoke with Biasco to learn more about the analyses of the analytical pipeline. He discussed their methods and the importance of the analysis.

Biasco L, Baricordi C, Loperfido M, et al. High throughput monitoring of safety, potency and stability of gene therapy cell products in lysosomal disease patients. Presented at: 18th Annual WORLDSymposium. February 7-11, 2022; San Diego, CA. Poster #26

The director of research and development at AVROBIO discussed the molecular follow-up of cell therapies. 

Performing In-Depth Analysis of Lentiviral Cell Therapies: Luca Biasco, PhD 

"I’m excited by [the data] but I want to be careful to not read too much into it until we have more more long-term data. But this is extremely encouraging. This is one of the first examples of intracisternal magna approach. And we're seeing that the procedure can be done safely and can have a remarkable impact, both on biomarkers and clinically."

Intracisternal magna administration of PBGM01 has demonstrated preliminary efficacy in achieving and regaining developmental milestones in GM1 gangliosidosis in the first 2 children dosed in the phase 1/2 IMAGINE-1 trial (NCT04713475). These data were presented by David Weinstein, MD, senior vice president, clinical development, Passage Bio, at the 

18th Annual WORLDSymposium, February 7-11, 2022 in San Diego, CA.

Investigators observed no serious adverse events (AEs) and mostly mild AEs unrelated to treatment. Both patients dosed exhibited substantial (1.5- and 4.8-fold) and durable increases in cerebrospinal fluid CSF β-gal, as well as stabilized or decreased GM1 ganglioside levels. Investigators also observed developmental gains substantially differing from natural history on the Vineland-II and Bayley-III scales. The first patients in the second (early-onset) and third cohort (high-dose) have now also been dosed.

spoke with Weinstein to learn more PBGM01 and the IMAGINE-1 trial. He discussed the positive safety findings and the initial efficacy seen so far in the trial, including promising biomarker activity.

Weinstein DA, Day-Salvatore DL, Ficicioglu C, et al. Safety, biomarker and preliminary efficacy results following ICM administration of PBGM01 in children with late onset infantile GM1-gangliosidosis. Presented at: 18th Annual WORLDSymposium, February 7-11, 2022; San Diego, CA. Poster #LB-71

The senior vice president of clinical development at Passage Bio discussed biomarker activity seen in the IMAGINE-1 trial. 

Cautious Optimism for GM1 Gangliosidosis Gene Therapy: David Weinstein, MD 

Homology Medicines is assessing their gene therapy candidate HMI-203 for the treatment of Hunter syndrome (mucopolysaccharidosis type 2; MPS II) in the open-label phase 1 juMPStart trial (NCT05238324).

The juMPStart trial design was presented atthe 

, February 7-11, 2022, in San Diego, California, by Jacinthe Gingras, PhD, senior director, ophthalmology and neurology, Homology Medicines.

“These presentations highlight how Homology’s gene therapy approach to Hunter syndrome and other lysosomal storage diseases is developed to target both the peripheral as well as the central nervous system manifestations of these multi-organ disorders,” Albert Seymour, PhD, chief scientific officer, Homology Medicines, said in a statement.

“We designed the juMPStart clinical trial with our 1-time, systemic gene therapy candidate by incorporating data and feedback we generated from our investigational new drug-enabling studies, as well as patient, caregiver and physician feedback. We believe that HMI-203 has the potential to address the peripheral and CNS challenges of Hunter syndrome that are not addressed by standard of care enzyme replacement therapy (ERT), and that a one-time intravenous (IV) administration would be a major advance for patients and their families.”

The juMPStart trial will evaluate 3 dose levels of a 1-time, intravenous administration of HMI-203 in adult men with MPSII, with up to 3 participants in each cohort.

The primary endpointissafety, determinedby adverse events (AEs) and serious AEs.

 Second Phenylketonuria Gene Therapy Study Put on Clinical Hold

Gingras outlined additional endpoints during her presentation, stating that “the selected endpoints include weekly plasma I2S activity and urinary glycosaminoglycan (GAG) levels will also be assessed. The effects of HMI-203 will be evaluated on peripheral disease manifestations including ambulation, liver and spleen volume, cardiac, and pulmonary function. In addition, evaluation of range of motion, sleep apnea and quality of life, as well as cerebrospinal fluid enzyme activity and GAG levels, will be evaluated to better understand the crossing of HMI-203 through the [blood-brain barrier].”

The trial design was informed by patient and physician perspectives, collected in interviews, and these perspectives were also presented at the symposium by Jeffrey Haroldson, senior director, global medical affairs, Homology Medicines.

Investigators interviewed 9 adults with MPSII and 6 physicians with significant clinical and research experience with the disease to further understand the disease burden of MPSII, the perspective of the current treatment landscape, and to understand expectations for gene therapy treatments.

“When we were asking the patients what were some of the symptoms not being treated [with enzyme replacement therapy (ERT)] that were really impacting their life, the top 3 answers were limited range of motion, pain, and heating loss. We also learned along the way that the patients report anxiety related to the uncertainty of the disease progression in addition to life expectancy,” Gingras noted in her presentation.

Patients reported a desire for a 1-time gene therapy that would address these symptoms more effectively than ERT. Physician input on clinical trial endpoints also lined up with these needs and informed the selected endpoints previously noted, including mobility tests and pulmonary and cardiac function tests. Physicians also agreed that a large unmet need with ERT is addressing fatigue and effects on the skeletal system.

Physician and patient perspectives on disease burden did differ, as physicians regarded surgical procedures and complications as the biggest burdens of disease while patients stressed constant pain as a more burdensome symptom.

1. Homology Medicines announcespresentations on HMI-203 investigationalgenetherapy for Hunter syndrome and broad applicability of AAVHSC platform for lysosomalstoragedisorders at the 18th Annual WORLDSymposium™ meeting. News release. Homology Medicines. February 10, 2022. 

https://www.globenewswire.com/news-release/2022/02/10/2383122/0/en/Homology-Medicines-Announces-Presentations-on-HMI-203-Investigational-Gene-Therapy-for-Hunter-Syndrome-and-Broad-Applicability-of-AAVHSC-Platform-for-Lysosomal-Storage-Disorders-at.html


2. Gingras J, Haroldson J, Smith LJ, et al. Clinical trial design for HMI-203 investigational gene therapy for mucopolysaccharidosis type II (MPS II) informed by cross-correction potential and KOL input. Presented at: 18th Annual WORLDSymposium, February 7-11, 2022; San Diego, CA. Poster #93
3. Haroldson J, Witalisz C, Mayfield C, et al. Patient and physician perspectives inform clinical trial design for a single intravenous dose of HMI-203, a gene therapy candidate for adults with mucopolysaccharidosis type II (MPS II, Hunter syndrome). Presented at: 18th Annual WORLDSymposium, February 7-11, 2022; San Diego, CA. Poster #118

The trial design was informed by both patient and physician perspectives. 

Patient-Informed Study to Evaluate Hunter Syndrome Gene Therapy 

Lysogene’s gene therapies, which includeLYS-SAF302 for the potential treatment of mucopolysaccharidosis type 3A (MPSIIIA) and LYS-GM101 for the potential treatment of GM1 gangliosidosis, have continued to show safety and efficacy in their respective indications.

Lysogene presented data on both programs at the 

, February 7-11, 2022 in San Diego, California. Lysogene’s chief scientific officer, Ralph Laufer, PhD, presented biomarker data on LYS-SAF302 and Karen PignetAiach, founder, chair, and chief executive officer of Lysogene presented safety data on LYS-GM101.

“Lysogene is developing an AAVrh10 vector for intraparenchymal gene therapy of this disease that contains the SGSH cDNA... the clinical development program consisted of a phase 1 trial (NCT01474343) that was conducted several years ago with a first-generation product called LYS-SAF301 that was conducted in 4 patients demonstrating safety and tolerability, the P3 study (NCT02746341), which was a prospective, non-interventional natural history study, and AAVance (NCT03612869), which is a phase 2/3 open-label clinical trial with our second-generation therapy LYS-SAF302 and its sister video study called PROVIDE,” Laufer said during his presentation.

The AAVance study has treated 19 patients with intraparenchymal injection of the gene therapy. As previously disclosed, white matter abnormalities associated with treatment have been observed near the injection sites and stabilized and improved from 12 months onwards with no clinically significant, directly attributable symptoms. The program remains on hold due to these changes but is minimally affected since 19 of 20 planned patients were already enrolled and treated. One patient has died 18 months after treatment, but this was deemed unrelated to LYS-SAF302 treatment.

Gene Therapy for GM1 Gangliosidosis: Latest Updates

Cerebrospinal fluid reductions of heparin sulfate and GM2/3 ganglioside were observed. The reductions are promising as these enzymes are thought to contribute to neuronal damage in MPSIIIA. Laufer discussed how axonal damage biomarkers did increase from baseline to 6 months, possibly reflecting local damage induced by intracranial administration or disease progression but declined after 6 months, reaching baseline levels at 12 months and levels below baseline from 18 months onwards.

Aiach presented updated safety data on LYS-GM101 which showed that the therapy was well tolerated with no adverse events (AEs) related to the therapy or intraparenchymal administration in the first 2 participants dosed with 2.0 x 

12 vg/mL. Based on these data, 2 additional participants are set to be treated with the therapy in early 2022, completing the firstsafety cohort part of the study.

Safety cohort data will be reviewed by the data safety monitoring board once available for all 4 patients in order to start making plans for the phase 2 part of the study, which expects to enroll at least 12 more participants. Efficacy data will be compared to published historical natural history data with matched assessment tools as well as to ongoing natural history studies and registries.

“There is no disease-modifying therapy currently available for GM1 gangliosidosis. Effective treatment is expected to be achieved by delivery of active β-gal protein to the CNS including the spinal cord, where the major pathology is observed,” Aiach said during her presentation.

1. Laufer R, Drevot P, Hocquemiller M, et al. AAVance gene therapy study in children with mucopolysaccharidosis type IIIA. Presented at: 18th Annual WORLDSymposium, February 7-11, 2022, San Diego, CA.
2. Frapaise FX, Aiach K. A study of intracisternal administration of adeno-associated viral vector serotype rh.10 carrying the human β-galactosidase cDNA for the treatment of GM1 gangliosidosis: Preliminary results of the safety cohort. Presented at: 18th Annual WORLDSymposium, February 7-11, 2022, San Diego, CA.

Updated data were presented on LYS-SAF302 and LYS-GM101 at WORLDSymposium. 

Lysogene Gene Therapies Show Promise in GM1 Gangliosidosis and MPSIIIA 

“As you would study the pharmacokinetics of chemical drugs, you need to also monitor the biodistribution and dynamics of these cells, with the added complexity that these cells are a much more complicated vehicle for therapies."

AVROBIO is improving on molecular follow-up of lentiviral cell therapies in patients with lysosomal disease with an analytical pipeline that evaluates cell therapy destiny and distribution. An overview of the pipeline was presented at the 

, February 7-11, 2022 in San Diego, CA, by Luca Biasco, PhD, director, research and development, AVROBIO.

Biasco and colleagues conducted high-resolution cellular and molecular studies and bone marrow and peripheral blood before and after lentiviral cell therapy treatment as part of the analytical pipeline. They analyzed the subpopulations of bone marrow and peripheral blood cells via digital PCR-vector copy number and integration site analysis, as well as clonal tracking data to elucidate the dynamics and destiny of cell populations after gene therapy.

 spoke with Biasco to learn more about the analytical pipeline. He discussed the advantages of analyzing subpopulations of peripheral blood and bone marrow over analyzing whole blood and bone marrow samples.

The director of research and development at AVROBIO discussed the analytical pipeline the company has developed for molecular follow-up of cell therapies. 

The Need for Analysis in Lentiviral Cell Therapies: Luca Biasco, PhD 

“We hope to reach a point where patients will have only 1 stem cell gene therapy transplant that could potentially address all the complications and unmet needs in cystinosis.”

CTNS-RD-04 is an autologous, lentiviral, CD34+ cell therapy developed by AVROBIO encoding for cystinosin for the potential treatment of cystinosis. The therapy, developed by the lab of Stephanie Cherqui, PhD, associate professor, University of California – San Diego, is being evaluated for safety and efficacy in a phase 1/2 trial (NCT03897361).

Interim data from the first 3 patients treated in the trial were presented by Cherqui at 

, February 7-11, 2022, in San Diego, California. No treatment-related adverse events (AEs) or serious AEs have been reported. All patients exhibited a decrease in white blood cell cystine and are no longer taking oral cysteamine. Promising decreases in cystine were also noted in the cornea, skin, and kidneys.

spoke with Cherqui to learn more about the gene-edited cell therapy that her lab has developed. She discussed the need for curative therapies in cystinosis and the potential of gene and cell therapies to fulfill this need.

The associate professor from UC San Diego discussed the curative potential of gene therapy in cystinosis. 

The Potential Impact of Gene and Cell Therapy in Cystinosis: Stephanie Cherqui, PhD

A first in-human, phase 1/2 study (NCT04771416) is evaluating intracisternal magna (ICM) administration of PBKR03 (Passage Bio), an investigational gene therapy in children with early infantile 

, February 7-11, 2022, in San Diego, California, by Eric J. Mallack, MD, assistant professor of pediatrics and neurology, and director, leukodystrophy center, Weill Cornell Medical College.

“PBKR03 is an investigational gene therapy developed by Dr. Wilson at the University of Pennsylvania. It carries a functional GALC gene... It is designed to transduce both CNS and PNS to generate functional GALC to break down and restore normal myelin metabolism and to cross correct neighboring cells,” Mallack, who is also an assistant attending at New York-Presbyterian Hospital and assistant attending neurologist at Memorial Sloan Kettering Cancer Center, said during his presentation.

The trial is now recruiting up to 24 participants with early infantile Krabbe disease who are between 1 to 9 months of age. Dose-escalation cohorts will be separated by age. Two dose levels—1.5 x 10

 GC/g—will be evaluated over the study duration of 2 years with 3 years of follow-up. Trial sites are now open in the US and Canada and will soon open in Brazil, Israel, the Netherlands, and the UK. 

Study to Evaluate Gene-Edited Cell Therapy for MPSII

Investigators will assess efficacy of PBKR03 based on longitudinal neurodevelopmental evaluations including the Bayley Scale of Infant and Toddler Developmnent, the Vineland Adaptive Behavior Scale-II, and a quality-of-life assessment including ventilator-free survival and feeding tube placement. Secondary outcomes will assess neurophysiological and neuroimaging assessments, investigational biomarker analysis, such as GALC activity in blood and cerebrospinal fluid and markers of disease progression, and quality-of-life assessments. Major analyses will be completed at 2- and 5-years post-treatment.

“Krabbe disease is even more devastating then GM1, these children oftentimes don't even make it to a few months of age before they deteriorate. So, the trial has sites throughout the world... to try to make sure that we can recruit children and treat them as soon as possible and make it as easy as possible for the family. The trial is now active in the United States and in Canada. We plan on showing results from that trial, we hope, in future meetings,” David Weinstein, MD, senior vice president, clinical development, Passage Bio, told 

 on Passage Bio’s GM1 gangliosidosis program at WORLDSympoiusm. The data, from the phase 1/2 IMAGINE-1 trial (NCT04713475), demonstrated that ICM administration of PBGM01 had efficacy in achieving and regaining developmental milestones in the first 2 children with GM1 gangliosidosis.

1. Mallack EJ, Jones SA, Aran A, et al. A phase 1/2 open-label, multicenter, dose ranging and confirmatory study to assess the safety, tolerability and efficacy of PBKR03 administered to pediatric subjects with early infantile Krabbe disease (globoid cell leukodystrophy; GALax-C). Presented at: 18th Annual WORLDSymposium, February 7-11, 2022; San Diego, CA. Poster #189
2. Weinstein DA, Day-Salvatore DL, Ficicioglu C, et al. Safety, biomarker and preliminary efficacy results following ICM administration of PBGM01 in children with late onset infantile GM1-gangliosidosis. Presented at: 18th Annual WORLDSymposium, February 7-11, 2022; San Diego, CA. Poster #LB-71

Passage Bio presented data on both the Krabbe and GM1 gangliosidosis programs at WORLDSymposium. 

First In-Human Trial to Assess Krabbe Disease Gene Therapy 

This content originally appeared on our sister site, 

The gene therapy AT845 (Astellas Pharma) has been well-tolerated in adult patients with late-onset 

 (LOPD), according to positive interim safety data from the phase 1/2 FORTIS study (NCT04174105) presented at the 

18th Annual WORLDSymposium, February 7-11, 2022, San Diego, CA.

FORTIS is an ongoing, multicenter, open-label, ascending dose trial assessing AT845, an investigational adeno-associated gene replacement therapy designed to deliver a functional 

 gene to express acid alpha glucosidase (GAA) directly into muscle cells. It is the first-in-human trial of the treatment.

The trial has enrolled 4 patients as of the December 3, 2021, cutoff date. Up to 24 weeks of follow-up data were reported for 2 patients in Cohort 1, who were dosed at 3 x 10

 vg/kg, and preliminary data was reported for 2 patients in Cohort 2, who were dosed at 6 x 10

 vg/kg. Reported safety data includes safety and tolerability assessments indicating that the treatment was well-tolerated in all participants.

“We are pleased that AT845 has been well-tolerated so far in the four adults with LOPD who have received treatment,” Weston Miller, MD, Senior Medical Director, Clinical Development, Astellas Gene Therapies, said in a statement.1 “In the 2 participants in Cohort 1 with follow-up duration through week 24 after dosing, AT845 demonstrated an encouraging safety profile.”

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Miller stated that, notably, there were no serious adverse events reported in any of the 4 participants thus far, adding, “One participant experienced elevated transaminases, which is considered a common immune-mediated treatment response based on the time of onset after dosing, its presentation during steroid taper initiation and its reversal with steroid re-initiation. These safety data are encouraging, and the program continues to enroll participants.”

Primary end points for the study included safety and efficacy of AT845 in this patient population, as well as efficacy, with investigators looking to observe change in muscle GAA protein expression and enzyme activity from baseline. Improvements in respiratory, endurance, and quality of life measures comprise the secondary end points. Participants in the FORTIS study receive a 1-time peripheral intravenous (IV) infusion of AT845, which is followed by 1 year of monitoring for safety, clinical, and biochemical end points. This includes GAA activity and protein level in patients’ muscles, as well as 4 additional years of long-term safety monitoring.

The only approved therapy for treatment of Pompe disease is enzyme replacement therapy (ERT). In August 2021, Sanofi announced that the FDA granted 

approval to avalglucosidase alfa-ngpt (Nexviazyme)

 for the treatment of LOPD in patients aged 1 year and older. The biologics license application for the long-term ERT was  

 in late 2020, after receiving breakthrough therapy and fast track designations. This treatment approach relies solely on tissue uptake of GAA from plasma and is delivered via biweekly IV infusions, with a recommended dose based on body weight—20 mg/kg for patients weighing 30 kg or heavier, and 40 mg/kg for those patients under 30 kg—and is administered incrementally via IV infusion.

“There is significant unmet need for patients with Pompe disease due to the short half-life, inefficient uptake in the key tissues affected by the disease and the immunogenicity of ERT,” Tahseen Mozaffar, MD, professor of neurology, pathology, and orthapaedic surgery; and director, Division of Neuromuscular Diseases, Neurology School of Medicne, UC Irvine, said in a statement.

“AT845 has the potential to be a best-in-class approach as a muscle-directed gene therapy using an AAV8 capsid serotype. It is being investigated to determine whether it can deliver a functional GAA gene that is efficiently transduced to express GAA directly in tissues affected by the disease, including skeletal and cardiac muscle.”

REFERENCES
1. Astellas announces positive safety data from the FORTIS study of AT845 in adults with late-onset Pompe disease. News release. February 7, 2022. Accessed February 8, 2022. https://www.biospace.com/article/releases/astellas-announces-positive-safety-data-from-the-fortis-study-of-at845-in-adults-with-late-onset-pompe-disease/
2. FDA approves Nexviazyme® (avalglucosidase alfa-ngpt), an important new treatment option for late-onset Pompe disease. News release. Sanofi Genzyme. August 6, 2021. Accessed February 8, 2022. https://www.sanofi.com/en/media-room/press-releases/2021/2021-08-06-17-42-21-2276588
3. FDA grants priority review for avalglucosidase alfa, a potential new therapy for Pompe disease. News release. Sanofi. November 18, 2020. Accessed February 8, 2022. http://www.news.sanofi.us/2020-11-18-FDA-grants-priority-review-for-avalglucosidase-alfa-a-potential-new-therapy-for-Pompe-disease

Interim safety data from the FORTIS study were presented at WORLDSympsoium.

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